Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the extra-pyramidal motor system. The hallmark pathology is degeneration of the dopaminergic neurons in the substantia nigra and loss of dopamine from the caudate nucleus. Most therapies involve elevating brain dopaminergic tone. The etiology of PD is not well understood. A recent twin study showed that, for PD with onset after age 50 (representing the majority of cases), the concordance rate was similar for mono- and dizygotic twins, suggesting that no highly penetrant gene was involved (Tanner et al, JAMA 1999; 281:341). However, PD has been linked to polymorphisms in several genes, typically involving dopamine metabolism or activation or detoxification of xenobiotics; these polymorphisms may affect genetic susceptibility to PD. Several lines of evidence support the hypothesis that PD has an environmental etiology. MPTP, a contaminant of synthetic heroin, caused a parkinsonian syndrome indistinguishable from PD in drug addicts. Animal and mechanistic studies of MPTP have clarified the pathophysiology of PD and suggested that environmental neurotoxicants are involved. Epidemiologic studies have demonstrated that PD risk is associated with rural living, well water drinking, farming, pesticides, and metals. In particular, several studies have shown that pesticide exposure is associated with increased PD risk although others have not. Inconsistencies among these reports, together with a lack of information on the relationship of PD to specific pesticides, constitute a data gap that motivated the present study. PD risk has also been associated with exposure to metals and with age, diet, and lifestyle factors including cigarette smoking, which is protective. An interesting potential risk factor is exposure to the soil pathogen Nocardia asteroides. This mycobacterium can cause nigral degeneration and an L-dopa responsive movement disorder in mice and monkeys. Exposure to Nocardia might present an explanation for the risk associated with rural living and farming, but human studies of PD and Nocardia exposure have been inconclusive. Our study is partly funded by an R01 grant awarded under an RFA on environmental determinants of PD issued by NIEHS and NINDS. It is a collaboration of Dr. Caroline Tanner (PI) and her colleagues at the Parkinsons Institute with members of the NIEHS Epidemiology Branch. The study is designed to evaluate five hypotheses: (i) that pesticide exposure increases PD risk; (ii) that exposure to other toxicants, particularly metals, increases PD risk; (iii) that Nocardia exposure increases PD risk; (iv) that diet and lifestyle risk factors previously identified in other populations have similar effects in this one; and (v) that PD risk is modified by genetic polymorphisms affecting metabolism of dopamine or xenobiotics. This study will be the first to use prospectively collected exposure information to evaluate the hypothesis that pesticide exposure is related to PD risk. It exploits the unique opportunity provided by the AHS to address this issue in an occupational group defined by pesticide use, combining rigorous methods of case-finding with several complementary methods of exposure assessment. Aims: To conduct a case-control study of PD nested in the Agricultural Health Study cohort, in order to determine whether increased risk of PD is associated with: - pesticide exposure - metal exposure - exposure to Nocardia asteroides, a soil microorganism - lifestyle factors including diet, cigarette smoking, and alcohol and caffeine use - polymorphisms in genes involved in xenobiotic metabolism, or gene-environment interactions The study will be a case-control study nested within the Agricultural Health Study, a large cohort study of 82,000 licensed pesticide applicators and their spouses. It will include ~160 cases and ~480 controls. This study is the first to investigate the relationship of pesticide exposure to PD prospectively, combining direct exposure measurements with detailed life histories of pesticide use. The study will have great power to address this issue, since virtually all cohort members are exposed to pesticides, although there is considerable variability within the cohort in exposure to specific chemicals. We have developed protocols and instruments for use in the field study. Twelve cases and 34 controls have been enrolled in the study.